Method for producing 3-trifluromethylphenyl-4-cyanobenzyl ketone

ABSTRACT

A process is described for preparing 3-trifluoromethylphenyl 4-cyanobenzyl ketone by reacting a C 1 -C 2 -alkyl 3-trifluoromethylbenzoate with 4-tolunitrile in an aprotic polar solvent or an aprotic polar solvent mixture in the presence of at least an equimolar amount of a base which is selected from potassium alkoxides of primary C 1 -C 4 -alkanols.

The present invention relates to a process for preparing3-trifluoromethylphenyl 4-cyanobenzyl ketone.

α-Phenylacetophenones such as 3-trifluoromethylphenyl 4-cyanobenzylketone (also referred to asα-(4-cyanophenyl)-3-trifluoromethylacetophenone) is an importantstarting material for preparing crop protection agents (cf., forexample, WO 00/18714).

JP 4168826 describes a process for preparing α-phenylacetophenones bycondensing optionally substituted benzoic esters with substitutedtoluenes in the presence of at least equimolar amounts of base. Thepreparation of 3-trifluoromethylphenyl 4-cyanobenzyl ketone by reactingone equivalent of methyl 3-trifluoromethylbenzoate with one equivalentof 4-tolunitrile in N,N-dimethylformamide is described explicitly.Sodium hydride functions as the base. The process described isproblematic from a safety standpoint, since reactions with sodiumhydride in N,N-dimethylformamide may result in vigorous thermaldecomposition reactions, cf. Chemistry & Engineering 1982, 5, July 12and 1982, 43, September 13. Also, sodium hydride is self-igniting underdamp air and reacts very vigorously with moisture to give hydrogen andsodium hydroxide solution. Therefore, the reactants and solvents usedmay have only an extremely low water content. However, the use of otherbases such as sodium tert-butoxide leads to worse yields compared tosodium hydride, as can be seen from the examples 3 and 3-2 whichdescribe the preparation of 3-chlorophenyl 4-cyanobenzyl ketone.

In-house investigations have also shown that of the other basesspecified in JP 4168826, the use of potassium carbonate inN,N-dimethylformamide results in no reaction, and the use of sodiumhydroxide in dimethyl sulfoxide results exclusively in hydrolysis of theester to the corresponding acid as a by-product.

To avoid these problems, WO 00/18714 suggests converting suchα-phenylacetophenones by reacting acetophenones with activatedhalobenzenes. A disadvantage of this is the moderate yield.

It is an object of the present invention to provide a technically safe,simple and economic process for preparing 3-trifluoromethylphenyl4-cyanobenzyl ketone which allows high yields of product of value to beachieved.

We have found that this object is achieved, surprisingly, and that3-trifluoromethylphenyl 4-cyanobenzyl ketone can be prepared in verygood yield under technically safe and mild reaction conditions where aC₁-C₂-alkyl 3-trifluoromethylbenzoate is reacted with 4-tolunitrile inan aprotic polar solvent or an aprotic polar solvent mixture in thepresence of at least equimolar amounts of potassium C₁-C₄-alkoxides of aprimary C₁-C₄-alcohol.

The invention therefore relates to a process for preparing3-trifluoromethylphenyl 4-cyanobenzyl ketone by reacting a C₁-C₂-alkyl3-trifluoromethylbenzoate with 4-tolunitrile in an aprotic polar solventor an aprotic polar solvent mixture in the presence of at least anequimolar amount of a base, wherein the base is selected from potassiumalkoxides of primary C₁-C₄-alkanols.

The potassium alkoxides of primary C₁-C₄-alcohols include potassiummethoxide, potassium ethoxide, potassium n-propoxide and potassiumn-butoxide. Preference is given to potassium methoxide.

In general, the base is used in an at least equimolar amount, based on4-tolunitrile. Preference is given to using from 1.1 to 5 equivalents ofbase, in particular from 1.5 to 4 equivalents, and most preferably from2.01 to 3 equivalents, of base, based on 4-tolunitrile.

A preferred C₁-C₂-alkyl 3-trifluoromethylbenzoate is methyl3-trifluoromethylbenzoate which is commercially obtainable.4-Tolunitrile is likewise commercially obtainable.

According to the invention, the reaction medium is an aprotic polarsolvent system which also includes mixtures of different aprotic, polarsolvents and mixtures of aprotic, polar solvents with aprotic, nonpolarsolvents. The proportion of nonpolar solvents will generally not exceed50% by volume, in particular 20% by volume. The proportion of aproticpolar solvents in the solvent to be used according to the invention istherefore generally at least 50% by volume and preferably at least 80%by volume. The examples of aprotic, polar solvents includeN,N-dimethylamides of aliphatic C₁-C₄-carboxylic acids such asN,N-dimethylformamide or N,N-dimethylacetamide, N-methyllactams such asN-methylpyrrolidone, dialkoxyalkanes such as 1,2-dimethoxyethane,diethylene glycol dialkyl ethers such as diethyl glycol dimethyl etheror diethyl glycol diethyl ether, sulfoxides such as dimethyl sulfoxide,sulfolane or tetraalkylureas such as tetramethylurea. In a preferredembodiment, at least one aprotic polar solvent is used as the solereaction medium (>99% by volume, based on the entire solvent mixture)and is preferably selected from 1,2-dimethoxyethane,N,N-dimethylformamide and dimethyl sulfoxide, among which particularpreference is given to N,N-dimethylformamide. Examples of preferredaprotic nonpolar solvents include aromatic hydrocarbons such as benzene,toluene or xylenes, cyclic hydrocarbons such as cyclohexane or aliphatichydrocarbons such as n-heptane, n-hexane, isohexane (commercial hexaneisomer mixture), decane and petroleum ether, although preference isgiven to aromatic hydrocarbons, in particular toluene and xylenes. Inanother preferred embodiment of the present invention, a solvent systemis used which, in addition to the aprotic polar solvent, especially inaddition to N,N-dimethylformamide, comprises from 1 to 50% by volume,preferably from 1 to 20% by volume and in particular from 2 to 15% byvolume, of at least one aprotic nonpolar solvent, in particular at leastone aromatic hydrocarbon and especially toluene and/or xylenes.Accordingly, the proportion of aprotic polar solvents in this mixture isfrom 50 to 99% by volume, preferably from 80 to 99% by volume and inparticular from 85 to 98% by volume. The addition of nonpolar solventsas an additive to the aprotic polar solvents eases the technicalhandling of the reaction and leads in particular to a reduction in theviscosity of the reaction mixtures and in addition suppresses undesiredfouling of tank walls and other apparatus parts such as stirrers andheat exchanger surfaces.

In general, the starting compounds 4-tolunitrile and C₁-C₂-alkyl3-trifluoromethylbenzoate are reacted with each other in an equimolarratio, although the ratio of the starting materials is of minorimportance for the success of the reaction. However, a relatively largeexcess of 4-tolunitrile is generally avoided, since it can lead to theformation of undesired by-products. In general, the molar ratio of4-tolunitrile to C₁-C₂-alkyl 3-trifluoromethylbenzoate will thereforegenerally not exceed a value of 2:1, in particular 1.5:1. However, it isalso possible, conversely, to use the ester in excess, although this isgenerally avoided for reasons of cost. The molar ratio of 4-tolunitrileto trifluoromethylbenzoic ester will therefore preferably not fall belowa value of 1:2 and in particular 1:1.5.

In a preferred embodiment, the molar ratio of the starting compounds4-tolunitrile and C₁-C₂-alkyl 3-trifluoromethylbenzoate will be about1:1, for example from 1.1:1 to 1:1.1.

The process according to the invention is generally performed attemperatures below 100° C., preferably not above 60° C., in particularin the range from +0 to 40° C.

The reaction pressure is of minor importance. Frequently, 4-tolunitrileis reacted with C₁-C₂-alkyl 3-trifluoromethylbenzoate in such a way thatthe solvent and the base are initially charged and the reactants arethen added separately or as a mixture and optionally heated. When thereactants are added in succession, preference is given to initiallyadding the nitrile and then the ester. By its nature, the reaction timedepends on the reaction temperature, reaction medium and base used andis generally in the range from 0.5 to 10 hours and in particular from0.5 to 5 hours.

The reaction can be carried out by a batchwise or semibatchwise method.

The reaction mixture is worked up and the product of value is removed bythe customary techniques, for example by hydrolyzing the potassiumenolate resulting from the reaction with aqueous acids such ashydrochloric acid, sulfuric acid or acetic acid, followed by anextractive workup. Any 3-trifluoromethylbenzoic acid formed as aby-product can be removed from the organic phase by alkaline extraction.The organic phase comprising the product of value may be used insubsequent reactions without further workup. Optionally, the solvent mayalso be removed to obtain the target compound in crystalline form.

The process according to the invention has a number of advantages overthe process described in JP 4168826. Firstly, the dangerous use ofsodium hydride in N,N-dimethylformamide can be dispensed with. Secondly,the organic phase comprising the product of value can be used insubsequent reactions immediately after the removal of the by-productformed, since the reaction mixture contains no interfering mineral oilfrom the sodium hydride. Also, the novel process is more economical,since relatively high yields of product of value are achieved even atrelatively low reaction temperatures. However, when sodium tert-butoxideor potassium tert-butoxide are used as base, higher reactiontemperatures are required and, in addition, the product of value isobtained in a worse yield.

The invention is illustrated by the examples which follow.

Preparation of 3-trifluoromethylphenyl 4-cyanobenzyl ketone.

EXAMPLE 1

In a reaction vessel, 10 equivalents of N,N-dimethylformamide wereinitially charged at 25° C. and 2.5 equivalents of potassium methoxidewere added with stirring at this temperature. At this temperature, first1 equivalent of methyl 3-trifluoromethylbenzoate and then 1 equivalentof 4-tolunitrile were then added. Reaction was allowed to proceed underthe conditions specified in Table 1.

When the reaction mixture was heated to temperatures above 25° C., thereaction mixture was initially allowed to cool to temperatures below 40°C. Afterwards, the reaction mixture was admixed within 15 minutes with 3equivalents of hydrochloric acid (10% by weight) and then with 25equivalents of toluene. After extraction and phase separation, theorganic extract was further extracted with 5% by weight aqueous sodiumhydroxide solution. The yields of the title compound are reported inTable 1. Temperature [° C.] Reaction time [h] Yield [%] 50 1.5 86 25 4.082 25 18.0 83

COMPARATIVE EXAMPLE 1

Example 1 was repeated, except that sodium methoxide was used instead ofpotassium methoxide. The reaction temperature was 25° C. and thereaction time was 25 hours. The title compound was obtained in a yieldof 75%.

COMPARATIVE EXAMPLE 2

Example 1 was repeated, except that sodium tert-butoxide was usedinstead of potassium methoxide. After a reaction time of 2 hours at 80°C., the title compound was obtained in a 71% yield.

COMPARATIVE EXAMPLE 3

Example 1 was repeated, except that 2.1 equivalents of solid potassiumtert-butoxide were used instead of 2.5 equivalents of potassiummethoxide. After a reaction time of 6.5 hours at 50° C. underatmospheric pressure, the title compound was obtained in a 69.6% yield.

1. A process for preparing 3-trifluoromethylphenyl 4-cyanobenzyl ketoneby reacting a C₁-C₂-alkyl 3-trifluoromethylbenzoate with 4-tolunitrilein an aprotic polar solvent or an aprotic polar solvent mixture in thepresence of at least an equimolar amount of a base, wherein the base isselected from potassium alkoxides of primary C₁-C₄-alkanol.
 2. A processas claimed in claim 1, wherein from 2.01 to 3 equivalents of base areused, based on 4-tolunitrile.
 3. A process as claimed in claim 1,wherein the aprotic polar solvent is selected from dimethylamides ofaliphatic C₁-C₄-carboxylic acids, N-methyllactams, tetramethylurea,dialkoxyalkanes, diethyl glycol dialkyl ethers and dimethyl sulfoxide.4. A process as claimed in claim 3, wherein the solvent isdimethylformamide.
 5. A process as claimed in claim 1, wherein theaprotic polar solvent mixture comprises from 1 to 50% by volume of anaromatic hydrocarbon.
 6. A process as claimed in claim 5, wherein theaprotic polar solvent mixture comprises dimethylformamide as the aproticpolar solvent and xylenes and/or toluene as the aromatic hydrocarbon. 7.A process as claimed in claim 1, wherein the reaction is carried out ata temperature in the range from 0 to 40° C.